Influence of inducible cross-resistance to macrolides, lincosamides, and streptogramin B-type antibiotics in Enterococcus faecium on activity of quinupristin-dalfopristin in vitro and in rabbits with experimental endocarditis

The influence of inducible cross-resistance to macrolides, lincosamides, and streptogramin B (MLS(B)) type antibiotics (inducible MLS(B) phenotype) on the activity of quinupristin-dalfopristin was investigated against Enterococcus faecium in vitro and in rabbits with experimental endocarditis. In vitro, quinupristin-dalfopristin displayed bacteriostatic and bactericidal activities against a MLS(B)-susceptible strain similar to those against two strains with the inducible MLS(B) phenotype. In addition, induction of the two MLS(B)-resistant strains with quinupristin (0.016 to 1 microg/ml) or quinupristin-dalfopristin (0.08 to 0.25 microg/ml) increased the MICs of quinupristin from 8 microg/ml to 32 to > 128 microg/ml, but did not modify the MIC of dalfopristin (2 microg/ml) or quinupristin-dalfopristin (0.5 microg/ml). In a rabbit endocarditis model, quinupristin-dalfopristin was as active as amoxicillin against the MLS(B)-susceptible E. faecium strain. In contrast, the activity of quinupristin-dalfopristin was significantly decreased in animals infected with either of the two inducible MLS(B)-resistant strains (P < 0.05), although no mutants resistant to quinupristin-dalfopristin were detected. Against the clinical strain with the inducible MLS(B) phenotype, quinupristin-dalfopristin was not effective and was less active than amoxicillin (P < 0.001); however, the activity of the combination of amoxicillin and dalfopristin-quinupristin was superior to that of amoxicillin (P < 0.01). The different impact of the inducible MLS(B) phenotype in E. faecium on the activity of quinupristin-dalfopristin in vitro and in experimental endocarditis may be related to the reduced diffusion of dalfopristin compared with that of quinupristin into cardiac vegetations that we previously reported. This result emphasizes the importance of the constant presence of dalfopristin at the site of infection to ensure synergism with quinupristin.